PathBank 2.0-the pathway database for model organism metabolomics.

PathBank (https://pathbank.org) and its predecessor database, the Small Molecule Pathway Database (SMPDB), have been providing comprehensive metabolite pathway information for the metabolomics community since 2010. Over the past 14 years, these pathway databases have grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in computing technology. This year's update, PathBank 2.0, brings a number of important improvements and upgrades that should make the database more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of primary or canonical pathways (from 1720 to 6951); (ii) a massive increase in the total number of pathways (from 110 234 to 605 359); (iii) significant improvements to the quality of pathway diagrams and pathway descriptions; (iv) a strong emphasis on drug metabolism and drug mechanism pathways; (v) making most pathway images more slide-compatible and manuscript-compatible; (vi) adding tools to support better pathway filtering and selecting through a more complete pathway taxonomy; (vii) adding pathway analysis tools for visualizing and calculating pathway enrichment. Many other minor improvements and updates to the content, the interface and general performance of the PathBank website have also been made. Overall, we believe these upgrades and updates should greatly enhance PathBank's ease of use and its potential applications for interpreting metabolomics data.

HMDB 5.0: the Human Metabolome Database for 2022.

The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.

Applications of Bone Morphogenetic Protein-2: Alternative Therapies in Craniofacial Reconstruction.

Large defects of the craniofacial skeleton can be exceedingly difficult to reconstruct since autologous bone grafts are limited by donor site morbidity and alloplastic implants have low biocompatibility. Bone morphogenetic proteins (BMPs) in craniofacial reconstruction have been used with mixed outcomes and complication concerns; however, results for specific indications have been promising.In alveolar clefts, cranial vault defects, mandibular defects, and rare Tessier craniofacial clefts, BMP-2 impregnated in collagen matrix was looked at as an alternative therapy for challenging cases. In cases where structural support was required, BMP-2 was used as part of a construct with bio-resorbable plates. Demineralized bone was added in certain cases.The authors described specific indications, detailed surgical techniques, and a review of the current literature regarding the use of BMP-2 in craniofacial reconstruction. BMP-2 is a viable option for craniofacial reconstruction to decrease donor-site morbidity or when alternatives are contraindicated. It is not recommended for routine use or in the oncologic setting but should currently be reserved as an alternative therapy for complex cases with limited options.Bone morphogenetic proteins are a promising, emerging option for complex craniofacial reconstruction. Future directions of BMP-2 therapies will become apparent as data from prospective randomized trials emerges.

Saving Lives at Birth; development of a retrospective theory of change, impact framework and prioritised metrics.

BACKGROUND: Grand Challenges for international health and development initiatives have received substantial funding to tackle unsolved problems; however, evidence of their effectiveness in achieving change is lacking. A theory of change may provide a useful tool to track progress towards desired outcomes. The Saving Lives at Birth partnership aims to address inequities in maternal-newborn survival through the provision of strategic investments for the development, testing and transition-to-scale of ground-breaking prevention and treatment approaches with the potential to leapfrog conventional healthcare approaches in low resource settings. We aimed to develop a theory of change and impact framework with prioritised metrics to map the initiative's contribution towards overall goals, and to measure progress towards improved outcomes around the time of birth. METHODS: A theory of change and impact framework was developed retrospectively, drawing on expertise across the partnership and stakeholders. This included a document and literature review, and wide consultation, with feedback from stakeholders at all stages. Possible indicators were reviewed from global maternal-newborn health-related partner initiatives, priority indicator lists, and project indicators from current innovators. These indicators were scored across five domains to prioritise those most relevant and feasible for Saving Lives at Birth. These results informed the identification of the prioritised metrics for the initiative. RESULTS: The pathway to scale through Saving Lives at Birth is articulated through a theory of change and impact framework, which also highlight the roles of different actors involved in the programme. A prioritised metrics toolkit, including ten core impact indicators and five additional process indicators, complement the theory of change. The retrospective nature of this development enabled structured reflection of the program mechanics, allowing for inclusion of learning from the first four rounds of the program to inform implementation of subsequent rounds. CONCLUSIONS: While theories of change are more traditionally developed before program implementation, retrospective development can still be a useful exercise for multi-round programs like Saving Lives at Birth, where outputs from the development can be used to strengthen subsequent rounds. However, identifying a uniform set of prioritised metrics for use across the portfolio proved more challenging. Lessons learnt from this exercise will be relevant to the development of pathways to change across other Grand Challenges and global health platforms.

Efficacy of WHO recommendation for continued breastfeeding and maternal cART for prevention of perinatal and postnatal HIV transmission in Zambia.

INTRODUCTION: To prevent mother-to-child transmission (MTCT) of HIV in developing countries, new World Health Organization (WHO) guidelines recommend maternal combination antiretroviral therapy (cART) during pregnancy, throughout breastfeeding for 1 year and then cessation of breastfeeding (COB). The efficacy of this approach during the first six months of exclusive breastfeeding has been demonstrated, but the efficacy of this approach beyond six months is not well documented. METHODS: A prospective observational cohort study of 279 HIV-positive mothers was started on zidovudine/3TC and lopinavir/ritonavir tablets between 14 and 30 weeks gestation and continued indefinitely thereafter. Women were encouraged to exclusively breastfeed for six months, complementary feed for the next six months and then cease breastfeeding between 12 and 13 months. Infants were followed for transmission to 18 months and for survival to 24 months. Text message reminders and stipends for food and transport were utilized to encourage adherence and follow-up. RESULTS: Total MTCT was 9 of 219 live born infants (4.1%; confidence interval (CI) 2.2-7.6%). All breastfeeding transmissions that could be timed (5/5) occurred after six months of age. All mothers who transmitted after six months had a six-month plasma viral load >1,000 copies/ml (p<0.001). Poor adherence to cART as noted by missed dispensary visits was associated with transmission (p=0.04). Infant mortality was lower after six months of age than during the first six months of life (p=0.02). The cumulative rate of infant HIV infection or death at 18 months was 29/226 (12.8% 95 CI: 7.5-20.8%). CONCLUSIONS: Maternal cART may limit MTCT of HIV to the UNAIDS target of <5% for eradication of paediatric HIV within the context of a clinical study, but poor adherence to cART and follow-up can limit the benefit. Continued breastfeeding can prevent the rise in infant mortality after six months seen in previous studies, which encouraged early COB.

Lateral incisor agenesis predicts maxillary hypoplasia and Le Fort I advancement surgery in cleft patients.

BACKGROUND: Severe maxillary hypoplasia in cleft patients is caused by a combination of pathogenic and iatrogenic factors. In this work, the authors investigated anatomical deficiencies in dentition for predicting Le Fort I maxillary advancement surgery for severe maxillary hypoplasia in cleft patients. METHODS: Cleft lip-cleft palate and cleft palate patients older than 14 years of age were reviewed for demographics, dental anomalies, and Le Fort I advancement. Chi-square tests, t tests, and multivariate logistic regression analyses were performed to delineate the contribution of quantity and position of dental agenesis to maxillary advancement surgery. RESULTS: In the 114 patients reviewed (mean age, 19.2 years), 64.0 percent were male patients, 71.9 percent had dental agenesis, and 59.6 percent required Le Fort I advancement. In patients who did not exhibit dental agenesis, 18.8 percent required Le Fort I advancement compared with 74.4 percent of patients with dental agenesis (p < 0.0001). Le Fort I advancement surgery was increased to 76.3 percent when dental agenesis was at the lateral incisor position (p < 0.0001) and 86.4 percent when patients were missing two or more teeth (p < 0.0001). Both sella-to-nasion-to-A point angle (p = 0.003) and A point-to-nasion-to-B point angle (p = 0.04) measurements were decreased in patients missing dentition at the lateral incisor position. Adjusting for multiple missing teeth and orthodontic compensations, multivariate logistic regression analyses demonstrated that lateral incisor agenesis is an independent predictor for Le Fort I advancement surgery (OR, 4.4; 95 percent CI, 1.42 to 13.64; p = 0.01). CONCLUSIONS: Lateral incisor agenesis correlated to maxillary hypoplasia and independently predicted the need for Le Fort I advancement in cleft patients, potentially as an anatomical readout of intrinsic growth deficiency. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Resorption of PDLLA plates as a nidus for recurrent langerhans cell histiocytosis.

Resorbable plating systems have been adapted into routine use for craniofacial reconstruction in children. After implantation in some patients, the area around the plates can develop palpable and visible fibrous capsules, with underlying bone resorption and a significant foreign-body giant cell reaction. The reaction is usually self-limited. We report a case in which Langerhans cell histiocytosis was resected, and then recurred at the sites of resorbing plate and screw placement in association with a foreign-body giant cell reaction.

Novel hyperactive glucocorticoid receptor isoform identified within a human population.

Glucocorticoids serve as important therapeutic agents in diseases of inflammation, but clinical use, especially in advanced septic shock, remains controversial because of the unpredictable response. Prior studies correlate human glucocorticoid receptor (hGR) isoforms with a decreased response to steroid therapy. Further analysis of additional hGR isoforms may improve the understanding of the steroid response. Ninety-seven human volunteers' blood samples were surveyed for hGR isoforms. An isoform matching National Center for Biotechnology Informatics (NCBI) hGRα (hGR NCBI) served as a reference. Two isoforms were of particular interest-one isoform had three nonsynonymous single-nucleotide polymorphisms (SNPs) (hGR NS-1), and the second had a single-nucleotide deletion (hGR DL-1) resulting in a truncated protein. Transactivation potentials were measured using a luciferase reporter assay. Human glucocorticoid receptor NS-1 had activity more than twice of hGR NCBI, whereas hGR DL-1 demonstrated less than 10% of the activity of hGR NCBI. Cotransfection of two isoforms revealed that the presence of hGR NS-1 increased transactivation potential, whereas hGR DL-1 decreased activity. Synthetic constructs isolating individual and paired SNPs of hGR NS-1 were created to identify the SNP responsible for hyperactivity. Transactivation studies revealed a SNP within the ligand-binding domain exerted the greatest influence over hyperactivity. In evaluating the response to hydrocortisone, hGR NCBI and hGR NS-1 displayed an increased dose-dependent response, but hGR NS-1 had a response more than twice hGR NCBI. Characterization of the novel hyperactive hGR NS-1 provides insight into a possible mechanism underlying the unpredictable response to steroid treatment.

Validation of the activity inventory of the Chedoke-McMaster stroke assessment and the clinical outcome variables scale to evaluate mobility in geriatric clients.

OBJECTIVE: To evaluate the construct validity of the Activity Inventory of the Chedoke-McMaster Stroke Assessment and the Clinical Outcome Variables Scale (COVS), 2 measures of functional mobility. DESIGN: A retrospective longitudinal study of 24 inpatients (mean age 83 years (standard deviation 7)) on a geriatric rehabilitation unit. PARTICIPANTS: The primary reasons for admission were deconditioning (n=9) and hip fracture (n=7). METHOD: We tested hypotheses that Activity Inventory and COVS scores at admission and discharge, and change scores during hospital stay would correlate. Longitudinal construct validity was also estimated using effect size and standardized response mean. RESULTS: Correlations between scores on each measure ranged from r=0.59-0.93 across subscales and total scales (p<0.01). The effect size of the Activity Inventory and the COVS was 1.53 and 1.43, respectively. The standardized response mean of the Activity Inventory and the COVS was 1.83 and 2.30, respectively. CONCLUSION: Although findings support the validity of both measures, the COVS appears more efficient and sensitive than the Activity Inventory to change in this population. A larger study is needed to confirm these findings.

The effect of CAG repeat length polymorphism in the murine glucocorticoid receptor on transactivation potential.

Severe sepsis remains an important cause of death, particularly among trauma and burn patients. The severity of the systemic inflammatory response after trauma or burns and susceptibility to sepsis vary among individuals. One possible mechanism is through differential effects on glucocorticoid receptor (GR) expression by pro-inflammatory mediators (e.g. lipopolysaccharide signaling). In a mouse burn model, we demonstrated differential GR levels, size, and transcriptional activity in CD14 knockout (KO) mice when compared to wild-type (C57BL/6J) after injury. Sequence analysis revealed only 8 CAG repeats in the GR transactivation domain in the CD14 KO; the wild-type contained seventeen. A survey of genomic DNA from 51 mouse strains demonstrated CAG repeat length range from 7 - 17. We then studied the effect of polymorphism in CAG repeat length on GR activity. Fragments with CAG repeats varying from 8-40 (8, 17, 30, 38, and 40) were engineered and shuttled into the wild-type GR expression vector. The resulting plasmids were then co-transfected with a glucocorticoid response element linked to a luciferase in order to compare their transactivation potentials. Transactivation potential was highest in the 17-CAG GR. The effect of GR polymorphisms on GR activity warrants more research as this data suggests a mechanism for the individual differences in response to steroid treatment and the response to injury.

Surgical management of groin lymphatic complications after arterial bypass surgery.

BACKGROUND: The authors undertook a retrospective study to define the incidence of groin wound lymphatic complications at their institution and to review their experience with treatment of the complications. METHODS: Operating room records and patient databases of the two primary vascular surgeons at an academic teaching institution were reviewed retrospectively. Groin lymphatic complications were diagnosed by clinical presentation and confirmed with noninvasive imaging. Surgical management included percutaneous methods, ligation of leaking lymphatics, excision, and/or muscle flap coverage. RESULTS: From June of 1989 to June of 2002, 538 patients had arterial revascularization procedures involving the groin. Twenty-seven patients with groin wound lymphatic complications were identified; seven of them had bilateral complications, for a total of 34 complication sites. Common comorbidities included hypertension, coronary artery disease, chronic renal insufficiency, and tobacco use. The majority (85 percent) had artificial material in the bypass graft, and 10 patients had undergone a previous operation at the same site. The mean time to identification of groin lymphatic complications after vascular surgery was 14 days. Common presentations included swelling (n = 16), drainage (n = 13), erythema (n = 4), and leg edema (n = 1). At presentation, 17 patients (63 percent) were receiving antibiotics and 21 (78 percent) were receiving anticoagulation or antiplatelet therapy. Of the 34 complication sites, 12 were managed with drainage or excision and 22 with muscle flap surgery, 10 of which failed less aggressive therapy. Muscle flaps included the gracilis (n = 19), sartorius (n = 1), rectus abdominis (n = 1), and rectus femoris muscles (n = 1). Operative cultures were positive in 23 of the 34 groin lymphatic complication sites. A biopsy specimen of a healed gracilis flap obtained at 1 year demonstrated notable lymphatic channels, possibly supporting theories that rotated muscle becomes a lymphatic conduit. CONCLUSIONS: The authors found that muscle flap surgery provides single-intervention therapy for successful resolution of lymphoceles, with a low complication rate and fairly rapid recovery in a high-risk patient population. Flaps also salvage cases that have failed conservative therapy and provide hardy coverage for a wound bed that is often infected.